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Tumor ABCC4-mediated release of PGE2 induces CD8+ T cell dysfunction and impairs PD-1 blockade in prostate cancer
Le Li1,2, Zheng Chao1,2, Hao Peng1
1Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Abstract:
Prostate cancer presents as an immunologically "cold" malignancy, characterized by a lack of response to immunotherapy in the majority of patients. The dysfunction of prostate tumor metabolism is recognized as a critical factor in immune evasion, resulting in reduced effectiveness of immunotherapeutic interventions. Despite this awareness, the precise molecular mechanisms underpinning metabolic dysregulation in prostate cancer and its intricate relationship with immune evasion remain incompletely elucidated. In this study, we introduce the multi-drug resistance protein ABCC4/MRP4 as a key player prominently expressed in prostate cancer, exerting a pivotal role in suppressing the activity of intratumoral CD8+ T cells. Depletion of ABCC4 in prostate cancer cells halts the release of prostaglandin E2 (PGE2), a molecule that diminishes the population of CD8+ T cells and curtails their cytotoxic capabilities. Conversely, constraining the activation of PGE2 signaling in CD8+ T cells effectively improved the efficacy of prostate cancer treatment with PD-1 blockade. During this process, downregulation of the JAK1-STAT3 pathway and depolarization of mitochondria emerge as crucial factors contributing to T cell anergy. Collectively, our research identifies the ABCC4-PGE2 axis as a promising target for reversing dysfunction within tumor-infiltrating lymphocytes (TILs) and augmenting the suboptimal responsiveness to immunotherapy in prostate cancer.
Insights
Prostate tumors evade immunotherapy by suppressing CD8+ T cells via ABCC4-mediated prostaglandin E2 (PGE2) release. Targeting this axis can restore T cell function and improve cancer treatment responses.
Area of Science:
- Oncology
- Immunology
- Cancer Metabolism
Background:
- Prostate cancer is immunologically "cold," limiting immunotherapy effectiveness.
- Tumor metabolic dysfunction contributes to immune evasion in prostate cancer.
- Molecular mechanisms linking prostate cancer metabolism and immune evasion are not fully understood.
Purpose of the Study:
- To identify key molecular players in prostate cancer's metabolic dysregulation and immune evasion.
- To investigate the role of ABCC4 in suppressing anti-tumor immunity in prostate cancer.
- To explore therapeutic strategies targeting the ABCC4-PGE2 axis for enhanced immunotherapy.
Main Methods:
- Investigated ABCC4 expression in prostate cancer.
- Assessed the impact of ABCC4 depletion on prostaglandin E2 (PGE2) release.
- Evaluated the effects of modulating PGE2 signaling on CD8+ T cell function.
- Analyzed the JAK1-STAT3 pathway and mitochondrial function in T cells.
- Tested the efficacy of PD-1 blockade with and without PGE2 pathway inhibition.
Main Results:
- ABCC4 is highly expressed in prostate cancer and suppresses intratumoral CD8+ T cells.
- ABCC4 depletion blocks PGE2 release, preserving CD8+ T cell numbers and cytotoxic activity.
- Inhibiting PGE2 signaling in CD8+ T cells enhances PD-1 blockade efficacy.
- T cell anergy involves JAK1-STAT3 downregulation and mitochondrial depolarization.
Conclusions:
- The ABCC4-PGE2 axis is a critical mechanism for immune evasion in prostate cancer.
- Targeting ABCC4 or PGE2 signaling can reverse T cell dysfunction.
- This axis represents a promising therapeutic target to improve immunotherapy response in prostate cancer.
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